PROJECT SUMMARY/ABSTRACT Skin cancers are the most common type of cancer in the United States. A primary etiologic agent for skin cancers is ultraviolet (UV) radiation, a carcinogen that induces DNA lesions, such as pyrimidine dimers. The risk of melanoma, a form of skin cancer with a poor prognosis, is also related to sun exposure. Understanding how human cells respond to and repair such DNA lesions is of clinical significance, especially for cancer prevention. As one of the physiologic responses to UV radiation, cells alter the expression of small, non-coding RNAs, known as microRNAs, which negatively regulate gene expression post-transcriptionally. Furthermore, some proteins involved in microRNA biogenesis are required for cellular resistance to UV. However, the molecular mechanisms connecting UV response signaling, the microRNA biogenesis machinery and repair of UV-induced DNA lesions are poorly understood. We hypothesize that UV-induced phosphorylation of human DGCR8, a double-stranded RNA binding protein in the microRNA processing complex, plays a critical role in the cellular response to UV. This is based on our novel finding that a serine residue of DGCR8 is phosphorylated in response to UV, and that this phosphorylation is critical for both cellular survival and efficient removal of pyrimidine dimers after UV irradiation. Surprisingly, the RNA-binding activity of DGCR8 is dispensable for cellular resistance to UV, suggesting an entirely new function of DGCR8 that is independent of microRNA processing. Further, we found that DGCR8 is epistatic with factors involved in transcription coupled-nucleotide excision repair and that recovery of RNA synthesis after UV exposure is delayed in DGCR8-deficient cells, suggesting that DGCR8 is involved in DNA repair of UV-induced lesions by participating in transcription coupled-nucleotide excision repair. We propose to elucidate the mechanisms by which DGCR8 regulates DNA repair of UV-induced lesions and to elucidate how the UV-induced phosphorylation of DGCR8 is regulated. Our studies will identify a novel cellular signaling pathway that connects the microRNA biogenesis machinery and UV-induced DNA damage and repair. We dub this the ?DGCR8-mediated UV response pathway?. Our work will provide mechanistic insights into the cellular UV response and, consequently, the rationale for novel approaches to cancer prevention. Finally, this work will uncover a new biological function of the microRNA biogenesis machinery that is separate from its canonical role.